SUMMARY The proposed research focuses on synthesis and analysis of a new type of agonist for B- family G protein-coupled receptors (GPCRs). This GPCR family collectively controls many important aspects of physiology. The natural agonists of B-family GPCRs are long polypeptide hormones (>27 residues); efforts to develop small-molecule agonists have been almost entirely unsuccessful for these receptors. Peptides that activate specific B-family GPCRs are used medicinally, including exenatide (39 residues), lixisenatide (45 residues) and liraglutide (30 residues) to treat type 2 diabetes, and teriparatide (34 residues) to treat osteoporosis. The type 2 diabetes drugs are agonists of the glucagon-like peptide-1 receptor (GLP-1R), and the osteoporosis drug is an agonist of the parathyroid hormone receptor 1 (PTHR1). We generate novel agonists by starting from a known agonist peptide, such as GLP-1(7-37) or PTH(1-34), and replacing a subset of the ?-amino acid residues with ?-amino acid residues, to generate ?/?-peptides. This backbone-modification strategy is distinct from and complementary to the more traditional approach of modifying ?-amino acid side chains. Inserting ? residues inhibits degradation by proteases, which was our original motivation for exploring the backbone- modification strategy. However, we have recently discovered that ??? replacement can alter the message conveyed by the peptide to its receptor, that is, this approach can generate biased agonists of the GPCR. Understanding and harnessing this feature of ?/?-peptide agonists is a major focus of the proposed research. Biased agonists are of great biomedical interest because they can be powerful tools for elucidating receptor function and the physiological outcomes of specific signaling pathways. In addition, biased agonists are attractive as drug candidates because they might minimize deleterious side-effects of receptor activation. The proposed research should advance our fundamental understanding of two important signaling networks, provide experimental design strategies that can be applied to other B-family GPCRs of medical interest, and perhaps lay a foundation for the development of a new type of therapeutic agent.